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WORLD INTELLECTUAL PROPERTY ORGANIZATION
International Bureau

PCX

INTERNATIONAL APPUCAHON PUBUSHED UNDER THE PATENT COOPERATION TREATY (PCT)

(51) fnternational P&tent ClassificBtion ^ :
A61B Sm, 5/05

(11) Intematioiial Publfcatioii Number: WO 99/39627

(43) International Publication Date: 12 August 1999 (12.08.99)

(21) International ApplicaUon Number: PCr/US98/02037

(22) IntemaUonal Filing Date: 4 Februaiy 1998 (04.02.98)

(71) Applicant (for ail designated States except US): DERMAL

THERAPY (BARBADOS) INC [BB/BB); 261 Bush Hfll.
Bay Street^ Bridgetown (BB).

(72) Inventors; and

(75) Inventors^Appiicants (for USonfy): ELDEN, Harry, Richard-
son [USAJ Sl; 55 00 S.W. 81 Tteace, Miami, FL 33143
(US). WICKETT, R., Randall [US/US]; 8351 Jakaro Drive,
Cincinnati. OH 45255 (US). OLLMAR* Stig [SE/SE];
Champljonvagen 51, S-14] 60 Huddlnge (SE). .

(74) Agent: MILLER, Charles, E.; Pennie & Edmonds LLP, 1 155
Avenue of the Americas, New Yoric. NY 10036-271 1 (US).

(81) Des^ted States: AL, AM, AT, AU, AZ, BA, BB. BO, BR,
BY, CA, CH, CN, CU, CZ, DE, DK, EB, ES, FI, GB, GB,
GH, CM, GW, HU, ID, O*, IS, JP, KB, KG, KP, KR, KZ,
LC, LK, Ul, LS, LT, LU. LV. MD, MO, MK, MN, MW,
MX. NO, NZ, PL, PT, RO, RU, SD^ SE, SO, SI, SK, SL,
TT, TM, TR, TT, UA, UO, US, UZ, VN, YU. ZW, ARIPO
patent (GH, GM, KB, LS. MW, SD, SZ, UG, ZW), Eurasian
patent (AM. AZ, BY, KG, KZ, MD, RU. TJ. TM), European
patent (AT, BE, CH, DE, DK. ES. H, FR, GB, <5R, IB, IT.
LU, MCI. NL, PT, SB), OAPI patent (BP. BJ, CP. CG, Q.
CM, GA. ON. ML, MR. NE, SN, TD, TG).

Pablished

Witii mtemaHonal search report.

(54) Htle: METHOD AND APPARATUS FOR NON-INVASIVE DETERMINATION OF GLUCOSE IN BODY FLUIDS
(57) Abstract

Method and apparatus for non-invaslvely determining glucose level in fluid of subject, typically Wood glucose level. Impedance of
skin tissue is measured and die measurement is used with impedance measurements previously conelated witfi directly deteiroined ghicose
levels to determine the ghicose level from die newly measured impedance. It is thus possible, to routinely non-invasively detemilne fluid
ghicose levels.

CM
CM
CU
CZ
DE
DK

FOJ? THE PURPOSES OP INFORMATION ONLY
Codes used to identily States party to fee PCT on the fhmt pa^

under the Per.

Albania

Aotrtl

AiBtTafit

Axnta^

Barbadot
BefgTnm
Bmidna Faso
Bi^garia
Benin

Central AlHcnRqpri^

Switzeriand
Cete<nvolre

CImia
Cuba

OechRqniblie

Spahi
Finland
Fkanoa
Gabon

United Kfaigdnn

Geoisii

Ghana

Guinea

Oicece

Hnqgaiy

Iceland

Itafy

Japan

Kyiggntstan
DemoctaiieFDople'a
RepabBc of Korea
R^mblic of Korea
Kazakstan
Saint Lnda
Lteditensteni
Sri Lanka
Liberia

LS
LT
LU
LV
MC
MD
MG
MK

LesoAo

Luxoubuuij

LaMa

Monaco

R^soUic of Moldova

Madagascar

Hio fenner Yqgoslnr

RepoUie of Macedonia

Mali

MoQgcHia

Mexico
Niger

Netheriands

Mn . ... . I .

worway
New Zealand

Romania

Rnsslan Fedci&tion

Smtan

Sweden

Skyveoia

SknnUa

Senegal

Swaziland

Chad

Togo

T^^kistan

T\u ktiienlslaa

IXiritcy

TT
UA

"niiniladandTobivD
Ubiina

United Staiea of Ameika

Uzbddstan

Viet Nam

Yii^ptlavn

ZImbdme

wo 99/39627

PCT/US98/02037

METHOD AND APPARATUS FOR
NON-INVASIVE DETERMINATION OF GLUCOSE IN BODY FLUIDS

FIELD OF THE INVENTION

The present invention relates to non-invasive methods and
5 devices for determining the level of glucose in a body fluid of a subject

BACKGROUND OF THE INVENTION

There are numerous reasons for determining the level of glucose
present in body fluid of a subject In the case of a person suffering from
diabetes, it is often necessary to determine the glucose level in blood daily, or

1 0 even more frequently. Non-invasive approaches to determination of blood
glucose levels have been suggested in the patent literature. For example,
United States Patent No. 5,036,861 (issued to Sembrowch et ai on August 6,
1991) describes a wrist-mountable device having an electrode which measures
glucose present in sweat at the skin surface. United States Patent No.

1 5 5,222,496 (issued to Clarke et al. on June 29, 1993) describes an infrared
glucose sensor mountable, for instance, on a wrist or finger. United States
Patent No. 5.433,197 (issued to Startc on July 18, 1995) describes
determination of blood glucose through illuminating a patient's eye with near-
infrared radiation. United States Patent Nos. 5,1 15,133, 5,146,091 and

20 5. 1 97,951 (issued to Knudson on May 1 9, 1 992, September 8, 1 992 and
January 1 9, 1 993, respectively) describe measuring blood glucose within
blood vessels of a tympanic membrane in a human ear through light
absorption measurements. The specifications of all of these patents are
incorporated herein by reference.

25 The most common cun-ent approaches to detennining blood

glucose levels still appear to involve obtaining a sample of the person's blood
and then measuring the level of glucose in the sample. These approaches will
not be reviewed here except to say that obtaining the blood sample
necessarily involves an invasive technique. Generally, the person's skin is

30 broken or lanced to cause an external flow of blood which is collected in some
fashion for the glucose level determination. This can be both inconvenient and

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dlstressful for a person and it is an object of the present invention to avoid the
step of obtaining a blood sample directly, at least on a routine or daily basis.

it is known that skin tissue, when immersed In an aqueous
glucose solution, equilibrates linearly with the concentration of external
5 glucose ("Glucose entry into the human epidemiis. I. The Concentration of
Glucose in the Human Epidennis", KM. Halprin, A. Ohkawara and K Adachi.
j. Invest. Dermatol., 49(6): 559. 1 967; "Glucose entry into the human
epidennis. II. The penetration of glucose into the human epidermis in vitro',
KM. Halprin and A. Ohkawara. J. Invest Derm., 49(6): 561, 1967). It has also

1 0 been shown that skin glucose can vary in synchrony with blood level glucose
during standardized tolerance testing in vivo ("The cutaneous glucose
tolerance test I. A rate constant fonnula for glucose disappearance from the
skin", R.M. Fusaro, JA Johnson and J.V. Pilsum, J. Invest Dennatol., 42:
359, 1 964; "The cutaneous glucose tolerance tesf , R.M. Fusaro and J A

15 Johnson, J. /nvesf. Dermatol. ,U: 230,1965). It Is also known for

equilibration of glucose levels to occur between blood and interetitlal fluids in

contact with blood vessels ("A microdlalysis method allowing characterization
of Intercellular water space in human", P. Lonnroth, P.-A Jansson and U.
SmWh, The American Journal of Physiology, 253 (Endocrinol. Metab., 16):

20 E228-E231 , 1 987; "Assessment of subcutaneous glucose concentration;
valldatton of the wick technique as a reference for implanted electrochemical
sensors in nomial and diabetic dogs," U. Fischer, R. Ertle, P. Abel, K Rebrin,
E, Brunstein, H. Hahn von Dorsche and E.J. Freyse, Diabetologia, 30: 940,
1987). Implantation of dialysis needles equipped with glucose sensors has

25 shown that orally ingested glucose load is reflected by parallel changes in skin
tissue glucose.

Radio firequency spectroscopy using spectral analysiis for //» v*d
or in vivo environments is disclosed in WO 9739341 (published October 23,
1997) and WO 9504496 (published Febmary 16. 1995). Measurement of a
30 target diemteai sudi as blood glucose is described.

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SUMMARY OF THE INVENTION

The present invention is a method and apparatus for non-
invasively monitoring levels of glucose in a body fluid of a subject. Typically,
blood glucose levels are determined in a human subject.
5 In a preferred embodiment, the invention is a method for non-

invasively monitoring glucose in a body fluid of a subject in which the method
includes steps of measuring impedance between two electrodes in conductive
contact with a skin surface of the subject and detemiining the amount of
glucose in the body fluid based upon the measured impedance. Typically, the
1 0 body fluid in which it is desired to know the level of glucose is blood. In this
way, the method can be used to assist In determining levels of insulin
administration.

The step of determining the amount of glucose can include
comparing the measured impedance with a predetermined relationship
1 5 between impedance and blood glucose level, further details of which are
described below in connection with pref en-ed embodiments.

In a particular embodiment, the step of detemnining the blood
glucose level of a subject includes ascertaining the sum of a fraction of the
magnitude of the measured impedance and a fraction of the phase of the
20 measured impedance. The amount of blood glucose, in one embodiment, is
determined according to the equation: Predicted glucose = (0.31) Magnitude +
(0.24)Phase where the Impedance is measured at 20 kHz.

in certain embodiments, impedance is measured at a plurality of
frequencies, and the method includes determining the ratio of one or more
25 pairs of measurements and detemiining the amount of glucose in the bocfy
fluid indudes comparing the detenriined ratio(s) with con-espond^^^
predetemnined ratib(s), i.e., that have been previously correlated with directly
measured glucose levels.

In certain embodiments, the method of the invention includes
30 measuring impedance at two frequencies and determining the amount of
glucose further includes determining a predetermined index, the index

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including a ratio of first and second numbers obtained from first and second of
the impedance measurements. The first and second numbers can include a
component of said first and second Impedance measurements, respectively.
The first number can be the real part of the complex electrical impedance at
5 the first frequency and the second number can be the magnitude of the
complex electrical impedance at the second frequency. The first number can
be the imaginary part of the complex electrical impedance at the first frequency
and the second number can be the magnitude of the complex electrical
impedance at the second firequency. The first number can be the magnitude of
10 the complex electrical impedance at the first frequency and the second number

can be the magnitude of the complex electrical impedance at the second
firequency. In another embodiment, detennining the amount of glucose further
includes determining a predetermined index in which the index includes a
difference between first and second numbers obtained from first and second of
15 said impedance measurements. The first number can be the phase angle of
the complex electrical Impedance at the first frequency and said second
number can be the phase angle of the complex electrical impedance at the
second frequency.

The skin site can be located on the volar foreamn, down to the
20 wrist, or it can be behind an ear of a human subject Typically; the skin
surface Is treated with a saline solution prior to the measuring step. An
electrically conductive gel can be applied to the skin to enhance
conductive c»ntact of the electrodes with the skin surface during the
niieasuing steiij.

25 The electrodes can be In operative connection with a computer

chip programmed to detennlne the amount of glucose in the body fluid based
upon the measured impedance. There can be an indicator pperatively
connected to the computer chip for indication of the determined amount of
glucose to the subject The Indicator can provide a visual display to the

30 subject

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In certain embodiments, the computer chip is operativisly .
connected to an insulin pump and the computer chip is programmed to adjust
the amount of insulin flow via the pump to the subject In response to the
detemiined amount of glucose.
5 Electrodes of a probe of the invention can be spaced between

about 0.2 mm and about 2 cm from each other.

In another aspect, the invention is an apparatus for non-invasive
monitoring of glucose in a body fluid of g subject. The apparatus includes
means for measuring impedance of skin tissue in response to a voltage

1 0 applied thereto and a microprocessor operatively connected to the means for
measuring impedance, for detemiining the amount of glucose in the body fluid
based upon the impedance measurement(s). The means for measuring
impedance of skin tissue can include a pair of spaced apart electrodes for
electrically conductive contact with a skin surface. The microprocessor can be

1 5 programmed to compare the measured impiedance with a predetermined
correlation between Impedance and blood glucose level. The apparatus can
Include means for measuring impedance at a plurality frequencies of the
applied voltage and the programme can include means for detemnining the
ratio of one or more pairs of the impedance measurements and means for

20 comparing the detenmined ratlo(s) with corresponding predetermined ratio(s) to
determine the amount of glucose in the body fluid.

The apparatus preferably includes an indicator operatively
connected to the microprocessor for indication of the determined amount of
glucose. The indicator can provide a visual display for the subject to read the

25 determined amount of glucose. It Is possible that the indicator would indicate if
the glucose level is outside of an acceptable range.

In a particular embodiment, the microprocessor is operatively
connected to an insulin pump and the apparatus includes means to adjust the
amount of insulin flow via the pump to the subject in response to the
30 determined amount of glucose.

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The apparatus can include a case having means for mounting the
apparatus on the foreamri of a human subject with the electrodes in electrically
conductive contact with a skin surface of the subject

In a particular embodiment, the apparatus includes means for
5 calibrating the apparatus against a directly measured glucose level of a said
subject. The apparatus can thus include means for Inputting the value of the
directly measured glucose level In conjunction with Impedance measured
about the same time, for use by the programme to determine the blood glucose
level of that subject at a later time based solely on subsequent impedance
10 measurements.

A microprocessor of the apparatus can be programmed to

determine the glucose level of a subject based on the sum of a fraction of the
magnitude of the measured impedance and a fraction of the phase of the
measured impedance. In a particular embodiment, the apparatus is set to
15 measure impedance at 20 kHz and the microprocessor is programmed to
detennine the glucose level of a subject based on the equation: Predicted
glucose = (0.31 )Magnitude + (0.24) Phase;

BRIEF DESCRiPTION OF THE DRAWINGS

Prefenred embodiments of the inverition will now be described,
20 reference being had to the accompanying drawirigs, wherein:

Figure 1 shows plots of various indices as a function of time and
glucose concentration t^sed on impedance measurements taken on the skin
(SCIM) of a first diabetic subject Figure 1(a) shows MIX versus measurernent
number, the timing of the measurements being given in Table 1 . Figure 1 (b)
25 shows PIX versus measurement number. Figure 1(c) shows RIX versus
measurement number. Figure 1(d) shows IMIX versus measurement number.
The detemiinations of MIX, PIX. RIX and IMIX are described in the text

Figures 2(a), 2(b), 2(c) and 2(d) are simitar to Rgures 1(a) to
1 (d). respectively, but are based on impedance measurement taken on the
30 skin of a second diabetic subject.

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Figure 3 is a plot shoviring the reading (average of ten readings)
of a dermal phase meter as a function of directly detennined blood glucosis
concentration. Measurements were taken on a site on the left foreami (•) and
right forearm (+); and
5 Figure 4 is similar to Figure 3, but readings were taken at a

finger

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

A preferred method of the invention involves directly contacting a
subject's skin with an electrode, taking one or more impedance measurements
10 and determining the subject's blood glucose level based on the impedance
measurement(s). Preferably, there is a computer programmed to make the
diaterminatidh based on the impedance measurement(s). In one aspect, the
invention includes deriving a number of indices from one or more
measurements of impedence between poles of the electrode. The value(s) of
15 the one or more indices is an indicator of, i.e. correlates with, the subjects
blood glucose level.

Thus, the invention is illustrated below by laboratory feasibility
tests to establish that a correlation between one or more such index values
based on impedance measurement(s) and a subject's blood glucose level
20 exists. The tests were conducted using particular parameters, for example
innpedahce measurements obtained at a certain fi^uency or certain
frequencies, and particular indices were dervied therefrom. It will be
understood that other and/or additional frequencies may be found to be more
optimal and that other Indides may well be found to be more optimal.

25 EjaiDBl^

Each of two subjects was treated as indicated in Table 1 .
Impedance measurements were taken at the volar forearm using the "SCIM*
apparatus described below. Impedance measurements were taken at thirty-
one frequencies and four different indices were determined using two of the

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frequencies: 20 and 500 kHz. Directly measured blood glucose levels of each
subject are IrKiicated In Table 1 .

Table 1: Treatment Regimen of Subjects

Measurement No. -
time (minutes)

Blood Glucose
Measurement
Rrst Subject

Blood Glucose
Measurement

Second Subject

154

141

Ingest 50 g glucose

146

164

174

194

246

232

228

257

Ingest 50 g glucose

268

304

255

348

320

346

320

355

399

361

100

343

383

110

334

381

Rapid Insulin

4 units

8 units

administered

125

358

379

140

377

346

155

353

333

Four indices, iVIIX, PiX. RIX and IMIX were determined (see
below) and plotted as a function of time. Rissults are shown in Figures 1 and

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2, the data collected prior to the first glucose ingestion being assigned "CT on
the X-axis of each plot.

Spearman rank order correlation coefRcients were detemiined,
and are presented Table 2 and 3 for the first and second subjects,

5 respectively. A value of P^O.05 is often considered to be a satisfactory
correlation. As can be seen in Table 2, a satisfactory conrelation was obtained
for both the MIX and the IMIX Indices for the first subject. As can be seen in
Table 3, a satisfactory correlation was obtained for the MIX, PIX and IMIX
indices for the second subject. The value of P for the RIX index was very

10 dose to being satisfactory. It must be borne in mind that these values were
obtained from a small sample set and yet a clear indication of a satisfactory
conflation for more than one index has been obtained in these experiments.
Optimization of the parameters of frequency and the choice of index or indices
might well lead to a significant improvement on the results given here.

15 ' •

Table 2: Statistical Analysis of Relationship between Measured Glucose
Levels and Selected Indices for Rrst Subject

Spearman Rank Order Correlations

Paired Variables

Valid N

Spearman R

t(N-2)

Glucose Level & MIX

-.722719

-3.77028

0.002336

Glucose Level & PIX

.865832

6.23942

0.000030

Glucose Level & RIX

-.418980

-1.66372

0.120073

Glucose Level & IMIX

-.710833

-3.64385

0.002972

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Table 3: Statistical Analysis of Relationship between Measured
Glucose Levels and Selected Indices for Second Subject

Speanman Rank Order Correlations

Pair of Variables

Valid N

Spearman R

t(N-2)

Glucose Level & MIX

-.616622

-2.82405

0.014353

Glucose Level & PIX

.266547

.99712

0.336903

Glucose Level & RIX

-.477094

-1.95731

0.072133

Glucose Level & IMIX

-.607686

-2.75888

0.016260

10 The impedance measurements on vitiich the results shown in

Figures 1 and 2 are based were obtained using a Surface Characterizing

Impedance Monitor (SCIM) developed by Ollmar (United States Patent No:
5,353,802, Issued October 11, 1994; "Instmment evaluation of sidn initation",
P.Y. Rizvi, B.M/Monison, Jr., M.J. Grove and G.L Grove, COs/nefics &

15 Toiletries., ill: 39, 1996; •Electrical impedance Index in human sidn:
Measurements atter occlusion, in 5 anatomical regions and In mild Irritant
contact dennatitis', L Emtestam and S. Ollmar, Cont Derm, 28: 337, 1975;
•Electrical Impediance for estimation of irritation in oral mucosa and skin", S.
Ollmar, E. Eek, F. Sundstrom and L Emtestam, Medical Progress Through

20 Technology, 21: 29, 1995; "Electrical impedance compared with other non-
Invasive bloengineering techniques and visual scoring for detection of initation
In human slon^ S. Ollmar, l\l Nyren, 1.' Nicander and L Emtestam,
De/mato/. 130: 29, 1994; "ConBlalion of impedarice response patterns to
histological findings in Imtant slUri reactions induced by various surfactants", I.

25 Nicander.S. Ollmar, A Eek, B.LundhRozell and L Emtestam, B/«L J.

Dermatol. 134: 221, 1996) which measures bioeledrical Impedance of the skin
at multiple frequencies. The instmment is basically an AC-bridge fabricated
from standand laboratory instmments: a function generator, a digital
oscilloscope. Impedance references, and a driver for the probe.

^0 The indices plotted in Figures 1 and 2 were detennined as

follows:

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MIX (magnitude index) = BbsiZj/a^labs^ZsoMti)
PIX (phase index) = argCZaodJ - a/g(Z5oo)*fe)
RDC (real part index) = /?e(Z20kHj/abs(ZsookHz)

IMIX (imaginary part index) = /m(Z2oi«i)/a6s(Z5ooi(Hr)
5 wliere abs{Z,) is the magnitude (modulus) of the complex electrical impedance
at the frequency /, arg(Z,) the argument (phase angle) in degrees, Re{Z,) the
real part of the complex electrical impedance, and lm{Z,) the imaginary part of
the complex electrical impedance. The magnitudes and phase angles are
delivered by the instrument, and the real and imaginary parts are calculated

10 according to the elementary complex number relationships: Re{Z,) =
a6s(Z,)*costafp(Z,)l and //r?(Z,) = abs(Z,)*sin[arg(Z,)l.

The RIX reflects changes mainly In conductivity; the IMIX reflects
mainly reactance changes, which are of capacitive nature; the MIX reflects
changes along the length of the vector describing the Impedance in complex

1 5 space, which will be emphasized if the real and imaginary parts change in the
same direction and proportion; the PIX will be emphasized if the real and
imaginary parts change in different directions and/or in different proportions.

Prior to contacting a subject's skin with the electrode, the skin is
treated with a 0.9% saline solution by holding a soaked gauze against the

20 measurement site for about a minute and then wiping the site with a dry cloth.
The purpose of this step is to ensure adequate electrical coupling between the.
skin and tile probe (electrode) in order to reduce variability that may
introduced into the measurements by stfaturh comeumi. A person skilled in the
art wouki understand ttiat variations are possible, and more optimal pror

25 ^tment conditions may be obtainable.

Blood glucose levels were determined directly firorn a blood
sample using a lancet prick and measuring ttie blood glucose concentration
witii an Elite Glucometer according to manufecturer's instructions (Elite
Glucometer, Miles Canada, Diagnostics Division, Division of Bayer).

30 In a second set of experiments, 31 subjects were tested using tiie

SCIM apparatus. A baseline measurement was taken and standardized food

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packet ingested. Two additional impedance measurements were taken one
half hour and one hour atter the initial measurement and blood glucose levels
detennined directly. Multiple regression analysis was carried out on data
obtained at 20 kHz and relationship (1 ) established:

5 •.

Predicted glucose = (0.31) Magnitude + (0.24) Phase; F-5.5. p<0.005

The multiple R for the prediction was 0.33.

The SCIM instrument was used to measure impedance measured

10 at 31 different frequencies logarithmically distributed in the range of 1 kHz to 1
Mhz (10 frequencies per decade). Subsequent determinations were based, in
the first set of experiments, on two of the frequencies: 20 and SOOkHz; and in
the second set of experiments, 20 kHz only. It may be found in the future that
there is a more optimal frequency or frequencies. It is quite possible, in a

15 commercially acceptable instrument that impedance will be determined at at
least two frequencies, rather than only one. For practical reasons of
instiumentation, the upper frequency at which impedance Is measured is likely
to be about 500 kHz, but higher flrequendes, even has high as 5 MHz or higher
are possible and are considered to be within the scope of this invention.

20 RelaUonships may be established using data obtained at one, two or more
frequendes.

It may be found to be preferable to use an artificial neural
network to perform a non-lini9ar regression.

A prefen-ed instrument, specifically for detennining glucose levels
25 of a subject, includes a 2-pole measurement configuration that measures
impedance at multiple frequendes, preferably tvi«) well spaced ?p^
frequendes. The instrument indudes a computer which also calculates the

index or indices that correlate with blood glucose levels and determines the
glucose levels based on the corrlelation(s).

^ The invention is also illustrated by experiments that were carried

out with a dermal phase meter (DPM) available from Nova™ Technology

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Corporation of Gloucester. Massachusetts. Measurements were taken with the
dermal phase meter at two sidn sites, the foreami and the middle finger. The
scale of the meter is from 90 to 999. It is thought that a higher reading
indicates a higher degree of skin hydration. Blood glucose measurements
5 were also measured directly (Mgs/dL) using an Elite Glucometer determined
directly from a blood sample using a lancet prick and measuring the blood
glucose concentration according to manufacturer's instructions (Elite
Glucometer, Miles Canada, Diagnostics Division, Division of Bayer). Typical
results are shown in Figures 3 and 4. Measurements were taken at various

1 0 times to track changes in skin hydration from that present while fasting
overnight, attending ingestion of a typical meal for breakfast or lunch and
following a peak of blood glucose and decline to about 1 00 Mgs/dL

in these experiments, a probe sensor was placed against the skin
sinrfece and held lightly until the instrument indicated completion of data

1 5 acquisition. Time interval (latch time) for data acquisition was selected at zero
seconds (instantaneous). Other sujtable time pj^'ods can be anywhere 0 and
30 seconds, or between 0.5 and about 1 0 seconds, or between about 1 and 5
seconds or about 5 seconds. The results obtained using the demial phase
meter are plotted as function of blood glucose concentration in Figures 3 and

20 4, respectively. Each plotted point represents the average of 10

measurements using the dermal phase meter. Studies were performed In the
morning on fasting subjects. After baseline measurements on fasting, food
was ingested to raise blood glucose levels. Studies continued until blood
glucose levels declined to baseline levels.

25 Figures 3 iand 4 indicate that the Nova™ meter readinjg of the

skin increases with increasing blood glucose concentrBtion.

f n one aspect of ttie invention, electrodes of a device are placed
in conductive contact virtth a subject's skin in order to measure impedance (Z)
at various frequencies (f) In a range from a few Hertz (hz) (say 1 0 hz) to about

30 5 Mhz. A more typical range would be between 1 kHz and 1 Mhz, and more
likely between 5 kHz and 500 kHz. Electrodes of the device are electrically

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conniBcted to a metering device which indicates the impedance at a selected
frequency of applied voltage, as understood by a person skilled In the art. In a
particular embodiment, the device is programmed to operate at the selected
frequencies in rapid sequence. Alternative modes of operation are possible,
5 for example, the voltage can be rapidly Increased with time and Fourier
transformation carried out to obtain a frequency spectrum. Ratios of
impedance measured at various frequencies are determined and the blood
glucose level of the subject is measured directly. This process Is repeated at
different times so as to make the determination at a number of different

10 glLk:ose levels. In this way, ratios of impedance detemiined at particular
frequencies which are found to reproduclbly reflect a person's blood glucose
levels over a range of glucose levels are detennined. The ratios of measured
impedance at the selected frequencies can thus be con^elated with directly
measured glucose levels, that is, a plot In which logCZ^/Za) vs log (f) is a linear

15 con-elation, or an approximately linear correlation, Is determined. This
relationship Is then used to determine the blood glucose level of the person
directly from ratios of similarly obtained Impedance measurements, thus
avoiding an Invasive technique for obtaining the blood glucose level.
Impedance includes both resistance and reactance.

^ It may be found for a proportion of the population that there is a

universal set of impedance frequency ratios, thus avokJIng the necessity of
detenninlng individuaj correlations.

The general approach described for the foregoing aspect of the
invention can be used in connection with other indices based on impedance
25 measurements, such as MIX, PIX. RIX and IMIX described above.

It is Important, of coursa, to be able to reliably reproduce results
as much as possible In order for this type of device to be useful. To this end
ari appropriate skin site is chosen. Generally speaking, an undamaged skin
.. site and one that Is not heavily scarred would ba chosen. A skiri site having a
30 stratum comeum which Is less likely to deleteriously Interfere virtth the

measurements Is chosen. A likely possibility Is the volar forearm; down to the

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wrist, or behind an ear. the skin surface can be treated just prior to
measurement in order to render the stratum comeum more electrically
transparent by application, for example, of a physiological saline dressing for
about a minute. Excess liquid should be removed before application of the
5 probe.

Given the importance of reliable glucose level determinations in
setting insulin administrations, it is important that the invention be used only in
circumstances in which it is known that the approach described herein reliably
indicates glucose levels of a subject. It is possible that the invention would not

1 0 be suitable for use with a given proportion of the population or 1 00% of the
time with a given individual. For example, an individual may have a skin
condition which deleteribusly interferes with impedance measurements,
making it difficult to assume that impedance measurements can reliably
indicate a person's blood glucose level. For such a person, a different

1 5 approach to glucose level determination would be more suitable.

An apparatus that utilizes a neural netwdrt< to carry out analyses
based on impedance could be trained for a specific subject, or possibly a
group of subjects. An example of such a group of subjects might be subjects of
the same sex, belonging to a particular age group and within particular height

20 and weight ranges.

4 may be advantageous to optimize the spacirlg of the electrodes
of the probe. That is, it may found that the electrodes of a SCIM probe are too
close to each other to provide maximally reproducible results. An object of a
suitable probe is to have electrodes spaced firom each other to obtain optimal

25 penetration of current into tissue containing glucose in its Interstitial spaces. It
is expected thdt electnodes spaced somewhere between about 0.2 mm arid
about 2 cm are suitable.

Additionally, the use of a gel can improve skin-probe contact to
rtiore reliably produce useful measurements, as would be known to a person

30 skilled In the art, e.g., a gel comprising mostly water in combination with a

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thickener such as Cellusize. glycerin or propylene glycol as a moisturizer, and
a suitable preservative.

An apparatus for non-invasive monitoring of glucose in a body
fluid of a subject includes means for measuring impedance of skin tissue in
5 response to a voltage applied thereto, i.e. a probe. There is a computer
processor operatively connected to the means for measuring impedance for
detennining the bipod glucose level based upon one or more impedance
measurements. The microprocessor is programmed to calculate the blood
glucose level of a subject based upon impedance measurements takisn at one

10 or more frequencies. In a particular embodiment, a calcuation based upon
Impedance at a single frequency, along the lines of that shown In relationship
(1), is canied out by the processor. In another embodiment, the calculation
includes detemiining MIX and/or IMiX. The calculation might include
detennining PIX. The calculation might include detennlning RIX. It might be

1 5 necessary to calibrate an individual apparatus for use with a particular subject
In such case, the apparatus includes means for calibrating the apparatus
agajnst a directly measured glucose level of that subject The apparatus could
thus include means for inputting the value of the directly measured glucose
level in conjunction with impedance measured about the same time, for use by

20 the programme to determine the blood giucidse level of that subject at a later
time based solely on subsequent impedanca measLorements.

In one embodiment a meter is worn in whk::h a probe Is
continuously in contact vi/ith the skin and moisture buildup between occlusive
electrodes and the skin is sufficient to obtain useful measurements. The

25 device can be mountable on a person's forearm, much like a wristwatch. Such
an embodiment might not prove to be useful for all subjects.

As previously stated, it might be found to be necessary for a
meter to be calibrated individually, that is, it might be necessary to detennine
the relationship between ascertained impedwce rattos or index or indices of

30 interest, and blood glucose levels of an individual and base the operation of
the partfcular meter for that Individual on the relationship. To this end, a

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preferred monitoring device of the invention includes means for calibrating the
relationship between a directly measured blood glucose level and an index or
indices of interest

Because blood glucose level detemninations of the present

5 invention are non-invasive and relatively painless it is possible to make such
detemninations with a greater frequency than with a conventional pin-prick
method. In a partlculariy advantageous embodiment, blood glucose levels are
monitored quite frequently, say every fifteen or five, or even one minute or
less, and an insulin pump is interfaced with the meter to provide continual

10 control of blood glucose in response to variatioris of blood glucose levels
ascertained by means of the meter

the disclosures of all references, arid partlculariy the
specifications of all patent documents, referred to herein, are incorporated
herein by reference.

15 The invention riow having been described, including the best

mode currently known to the Inventors, the claims which define the scope of
the protection sought for the invention follow.

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CLAIMS

1 . A method for non-invasively monitoring glucose in a body fluid of a subject,
the method comprising:

measuring impedance between two electrodes in conductive contact with a
5 skin surface of the subject; and

determining thei amount of glucose in the body fluid based upon the
measured impedance.

2. The method of claim 1 wherein the body fluid Is blood.

3. The method of claim 2 wherein determining the amount of glucose includes
10 comparing the measured impedance with a predetermined relationship

between impedance and blood glucose level.

4. The method of claim 1 , 2 or 3 wherein the subject is human.

5. The method of claim 1 , 2 or 3, including measuring impedance at a plurality
of frequencies, detennining the ratio of one or more pairs of measurements

15 and wherein detennining the amount of glucose In the body fluid includes

comparing the detennined ratlo(s) with con-esponding predetenmined ratio(s).

6. The method of claim 5 wherein the skin swface Is kscated on the volar
forearm.

7. The method of claim 6 wherein the sWn surface is treated with a saline
20 solution prior to the measuring step.

8. The method of claim 7 wherein an electrically condudive gel Is applied to
the skin to enhance the conductive contact of the electrodes with the skin
surface during the measuring step.

9. The method of claim 1 , 2 or 3, wherein the electrodes are In operative
25 connection with a computer chip programmed to detennine the amount of

glucose in the body fluid based upon the measured impedance.

10. The method of claim 9 wherein an indicator is operatlvely connected to the

computer chip for indication of the determined amount of glucose to the

subject

30 1 1. The method of claim 10 wherein the Indicator provides a visual display to
the subject

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12. The method of daim 9 wherein the computer chip is operatively connected
to an insulin pump and the computer chip is further programmed to adjust the
amount of insulin flow via the pump to the subject in response to the
determined amount of glucose.
5 13. The method of claim 1, 2 or 3, wherein the electrodes are spaced between
about 0.2 mm and about 2 cm from each other.

14. The method of claim 1 wherein determining the amount of glucose
includes measuring impedance at two frequencies.

15. The method of claim 14 wherein determining the amount of glucose further
10 includes determining a predetermined index, the index comprising a ratio of

first and second numbers obtained from first and second of said impedance
measurements.

16. The method of claim 15 wherein each of said first and second numbers
includes a component of said first and second impedance measurements,

16 respectively.

17. The method of claim 16 wherein said first number is the real part of the
complex electrical impedance at the first frequency and the second number is
the magnitude of the complex electrical impedance at the second frequency.

18. The method of claim 16 wherein said first number is the imaginary part of
20 the complex electrical impedance at the first frequency and the second number

is magnitude of the complex electrical impedance at the second frequency.

1 9. The method of claim 1 6 wherein said first number is the magnitude of the
complex electrical impedance at the first frequency and said second number is
the magnitude of the complex electrical impedance at the second frequency.

25 20. The method of daim 14 wherein determining the amount of gluirose further
indudes determining a predetennlned index, the index comprising a difference
between first and second numbers obtained from first and second of said
impedance measurements.

21 . The method of daim 20 wherein said first number Is the phase angle of
30 ttie complex electrical impedance at the first frequency and said second

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number is the phase angle of the complex electrical impedance at the second
frequency.

22. The method of claim 1 or 2 wherein determining the amount of glucose
includes ascertaining the sum of a fraction of the magnitude of the measured

5 impedance and a fraction of the phase of the measured impedance.

23. The method of claim 2 including determining the amount of blood glucose
according to the equation of relationship (1 ).

24. An apparatus for non-invasive monitoring of glucose in a body fluid of a
subject, the apparatus comprising:

10 means for measuring impedance of skin tissue in response to an voltage
applied thereto; and

a microprocessor operatively connected to the means for measuring
impedance, for determining the amount of glucose in the body fluid
based upon the impedance measurement
15 25. The apparatus of claim 24, wherein said means for measuring impedance
of skin tissue includes a pair of spaced apart electrodes for electrically
conductive contact with a skin surface.

26. The apparatus of claim 25, wherein said microprocessor is programmed to
compare the measured impedance with a predetennined correlation between

20 impedance and blood glucose leve>l,

27. The apparatus of claim 26, Including mearis for measuring impedance at a
plurality fi'equdncles of said applied voltage, wherein the programme further
includes means for determining the ratk) of one or more pairs of the impedance
measurements and means for comparing the detennined ratio(s) with

25 corresponding predetermined ratlo(s) to determine the amount of glucose in
the body fluid

28. The apparatus of claim 24, 25, 26 or 27, further comprising an indicator
operatively connected to the microprocessor for indication of the determined
amount of glucose.

30 29. The apparatus of claim 28 wherein the Indfcator provides a visual display.

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30. The apparatus of claim 28 wherein the microprocessor is operativeiy
connected to an insulin pump and includes means to adjust the amount of
insulin flow via the pump to the subject in response to the determined amount
of glucose.

5 31. theapparatusof claim 25. 26 or 27 wherein the electrodes are spaced
between about 0.2 mm and about 2 cm from each other.
32. The apparatus of claim 28 including a case having means for mounting the
apparatus on the forearm of a human subject with the electrodes in said
electrically conductive contact with a skin surface of the subject.
10 33. The apparatus of claim 24, further comprising:

means for calibrating the apparatus against a directly measured glucose
level of a said subject

34. The apparatus of claim 25 or claim 33, wherein the microprocessor is
programmed to determine the glucose level of a subject based on the sum of a

15 fraction of the magnitude of the measured impedance and a fraction of the
phase of the measured impedance.

35. The apparatus of claim 34, wherein the microprocessor is programmed to
determine the glucose level of a subject based on the equation of relationship

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mXERNATIONAL SEARCH REPORT

Int .tional Application No

PCT/US 98/02037

A. CLASSIFICATION OF SUBJECT MATTER ,

IPC 6 A61B5/00 A61B5/05

Acooiding to Iftfgmational PatenI ClassiticattefmPC) or to bom national dassfficatten and IPC

B. FIELDS SEARCHED

Minimum documentation searched (dassricatlon system followed byctassificalion symbots)

IPC 6 A61B GOIN

Oocumentatlon searched other than mininiumdoGumeniaiion.to the extent that such documents are included In the fields searched

Eiedrontc data base consufted dunng the international search (name of data base and. where practical, search lemns used)

C DOCUMENTS CONSIDERED TO BE RELEVANT

Category - Citation of document with incScation. where appropnate^ of the relevant passages

RelevanitoclaimNo.

WO 93 18402 A (UNIVERSITY COLLEGE OF WALES
) 16 September 1993

see page 1, line 6 - page 3, line 32
see page 4, line 10 - page 6, line 25
see figures

WO 95 04496 A (SOLID STATE FARMS, INC.) 16

February 1995

cited In the application

see page 6, line 16 - page 8, line 2
see page 18, line 30 - page 19, line 14
see figure 1

1-4.6,7,
9,24-26,
33

1-4,
9-11.

24-26,
28,29

Further documents are Ostod In the continuation ol box C.

Patent famOy membefv are fisted in annex.

" Special categortes of cted documents :

*A' documei^ denning the gerierat state of the art which is not

considefod to be of paittcular relevance
"E" earfier document but put>fehed on or after the international

filing date

"L" documerl which may throw dotM on prtorfty claim(s) or
which is dted to estetilish the pubibafiondate of another
cftation or other speciai reason (as spedftod)

"O" document referring to an oral dlsdosure, use, exhSiWonor

T" documerl piMbhed prior to me Memailonalflttng date bul
later than the prforiy date claimed

T* later document published after the international nong date
or priority date and not in conffid wlh the application but
dted to understand the prfnc9>le or theory underlying the
invention

*X' document of paittcular relevance; the claimed invention
cannot be oonsiderBd novel or cannot be considered to
invohre an inventive step when the document is taken alone

• *Y* document of partictdar relevance; the claimed invention

cannot be considered to involve an inventive step when the
docunert is combined wfth one or more other such docu-
merla^ such conMnaUon being obvious to a pereon sMM
mtheait

*&* document member of the same patent famay

Dale of the actual oomplBtion of thelnlemaUonal search

15 June 1998

Date of mafflng ol the international search report

24/06/1998

Name arKi maOng address of the ISA

Ewopean Pateni Office. P.B. 5618 Patentlaan2
l^-2280KVR^wfk
Tel. (431-70) 340-204a Tx. 31 651 epo nl.
Fax: (431-70) 340-3016

Foon PCT/tSAOlO (ftacond tfiMQ (Jtfy tMZ)

Authorized officer

Chen, A

page 1 of 2

INTERNATIONAL SEARCH REPORT

Im Itlonai Application No

PCT/US 98/02037

C.(Contfnuallon) DOCUMENTS CONSIDERED TO BE RELEVANT

Category Cilation of docunwit. with incfcatloawtiere appropnata. of the relevant passages

Relevant to dam No.

ZAMZOW ET AL.: "Development and
evaluation of a wearable blood glucose
monitor"

ASAIO TRANSACTIONS,

vol. 36, no. 3, July 1990, TORONTO, CA,
pages 588-591, XP000204509
see page 588, right-hand column, line 1 ■
page 591, left-hand column, line 41
see figures 1,2

OE 19 34 139 A (FORSTER) 21 January 1971
see page 3, line 1 - page 8, line 11
see figure 1

10-12,
28-30,32

1.24

Foim PCr/tSA«10 (conlinuatfan of s«cond sheal) (July i992)

page 2 of

INTERNATIONAL SEARCH REPORT

Inlonnalion on patent lamBy members

Inb ' lionai Appiieation No

PCT/US 98/02037

Patent document -
cited in search report'

PubHcalion
. data

Patent family
member(s)

Publication
date

WO 9318402

16-09-1993

AU
CA
EP
JP
NO
US

662400 B

2127355 A
0629291
7504579
943114
5569591

A
T
A
A

31-08-1995
16-09-1993
21-12-1994
25-05-1995
23-08-1994
29-10-1996

WO 9504496

16-02-1995

OE 1934139

21-01-1971

US
AU
AU
EP

NONE

5508203 A
676082 B
7520294 A
0714259 A

16-04-1996

27- 02-1997

28- 02-1995
05-06-1996

FbonPCTASA/ZlOdsdKltxTAyamnrXJtiy 1802)

■ *

THISPASIStANKiuspro)

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Full text of "USPTO Patents Application 10687850"

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